Amyotrophic lateral sclerosis (ALS) is the most common progressive neurodegenerative motor neuron disease, causing damage to upper and lower motor neurons, leading to paralysis and death within 3-5 years. Riluzole remains the only effective drug for ALS, but extends the average survival of patients by only 3-6 months. Therefore, discovery of further effective disease-modified therapies is an ultimate aim.
Immunoglobulins of the IgG subtype activate an immune response by simultaneously binding antigens through their variable domains (F(ab)2) and through interaction of their Fc fragment with Fc receptors on immune cells. The human Fc receptor family includes the activating receptor FcyRIIIA (CD 16A) and FcyRIIIB (CD 16B) that mediates immune effector functions.
Analysis of glycosylation patterns of IgG from ALS patients revealed a distinct glycan, A2BG2, in IgG derived from ALS patient's sera. This glycan increases the affinity of IgG to CD 16 on effector cells i.e., microglia (Lichtenstein, et al. PLoS One. 2012; 7(5): e35772.)
Furthermore, the A2BG2 glycan was shown to be specific to ALS. The quantity of A2BG2 increases with disease progression. IgG antibodies identifying extracellular motor neurons are developed at late stages of the disease (Lichtenstein, et al. Exp Neurol. 2015 May; 267:95-106).
Microglial cells are phagocytes of the central nervous system (CNS) possessing similar phenotype as macrophages in the periphery. These cells express CD16 Fc receptors. Inhibition of CD16 mediated microglia activation has been suggested to have therapeutic value for the treatment of ALS, such as in US patent application US 2014\0328824.
Rituximab is a chimeric monoclonal antibody, which encompasses a mouse Fab domain with a CD20 antigenic-binding site and a human Fc fragment with engineered glycans to increase cytotoxicity. This increase was attributed to an increased affinity of the Fc fragment of rituximab to the CD16 Fc receptor (Weiner et. Al., Blood. 2006 Oct. 15; 108(8): 2648-2654).